CURRENT STANDARD OF CARE OF METASTATIC COLORECTAL CANCER: THE EVOLUTION OF ESMO CLINICAL
PRACTICE GUIDELINES
Fortunato Ciardiello
ESMO Past-President 2018-2019
Dipartimento di Medicina di
Precisione
Università degli Studi della
Campania Luigi Vanvitelli
CONFLICT OF INTEREST DISCLOSURE
Advisory Boards:
Roche, Amgen, Lilly, Merck, Servier, Bayer, Symphogen
Institutional Research Funding:
Roche, Amgen, Bayer, Merck
Drivers for first line treatment choices in
metastatic colorectal cancer
Adapted from Van Cutsem et al, ESMO Consensus Conference, Annals of Oncology 2016
• Clinical presentation (tumour burden, primary tumour localisation)
• Tumour biology
• RAS mutation status
• BRAF mutation status
*Tumour
Characteristics
• Age
• Performance status
• Organ function
• Comorbidities
• Patient attitude, expextations, preference
Patient
characteristics
• Toxicity profile
• Flexibility of treatment admnistration
• Socioeconomic factors
• Quality of life
Treatment
characteristics
*Additional tumour characteristics: HER2 amplification; MSI-H status
Twenty-one consensus reccomendation statements on diagnosis and
treatment options and sequences for oligometastatic as well as for
extended metastatic disease.
and
Three consensus reccomedation statements on the use of cytotoxics
and biologicals in the first and subsequent lines of treatment.
The results of the Consensus Conference
on metastatic colorectal cancer were summarized in:
Recommendation 3: RAS testing
RAS is a predictive biomarker for therapeutic choices involving EGFR antibody
therapies in the metastatic disease setting [1, A].
RAS testing is mandatory prior to treatment with EGFR-targeted monoclonal
antibodies cetuximab and panitumumab [1, A].
Primary or metastatic colorectal tumour tissue can be used for RAS testing (see
also Recommendation 3).
RAS analysis should include at least KRAS exons 2, 3 and 4 (codons 12, 13, 59,
61, 117 and 146) and NRAS exons 2, 3 and 4 (codons 12, 13, 59, 61 and 117).
Turnaround time for RAS testing (expanded RAS analysis) should be ≤7 working
days from the time of receipt of the specimen by the testing laboratory to the time of
issuing of the final report, for >90% of specimens.
Molecular Pathology and Biomarkers
Recommendation 5: BRAF testing
Tumour BRAF mutation status should be assessed alongside the assessment of
tumour RAS mutational status for prognostic assessment (and/or potential selection
for clinical trials) [I, B]
Recommendation 6: MSI testing
MSI testing in the metastatic disease setting can assist clinicians in genetic
counselling [II, B]
MSI testing has strong predictive value for the use of immune check-point inhibitors
in the treatment of patients with mCRC [II, B]
Molecular Pathology and Biomarkers
Recommendation 9: emerging technologies
Although CTC number correlates with prognosis in patients with mCRC, the clinical
utility of CTC assessments is not yet clear and therefore cannot be recommended
[IV, D].
The utility of liquid ctDNA biopsies to guide treatment decisions is currently under
investigation in clinical trials, but cannot yet be recommended in routine practice [V,
D].
Whole genome, whole exome and whole transcriptome analysis should be carried
out only in a research setting [V, D].
Molecular Pathology and Biomarkers
ESMO consensus guidelines for the management ofpatients with metastatic colorectal cancer
ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17
Final submission draft
18#
Table 1. Source of patients for the analyses
Trial name
Trial characteristics
Phase of trial
Chemo-therapy
backbone
Bevacizumab in control
arm?
Anti-EGFR therapy
Treatment line
Randomised With KRAS
evaluable
With KRAS
Wt*
With all RAS
wt
With all RAS wt and
tumour side confirmed
CRYSTAL [28, 42, 43]
III FOLFIRI No Cetuximab 1st
1217 1063 666 367%
364
FIRE-3
[28, 36]
III FOLFIRI Yes Cetuximab 1st
752 NA 609£ 400
%% 394
PEAK [35] II FOLFOX6 Yes Panitumumab 1st
285 285 285 170$
143
PRIME [40, 41]
III FOLFOX4 No Panitumumab 1st
1183 1096 656 512 416
20050181
[45]
III FOLFIRI No Panitumumab 2nd
1186 1083 597 421 368
CALGB
80405 [27, 38]
III FOLFIRI/
FOLFOX6
Yes Cetuximab 1st 1137 1137 1137 526
$$ 474
*Not always easy to determine, taken from publication or slide presentation. Sometimes refers to all ITT population (PRIME, PEAK, AMGEN181) sometimes from the KRAS wt exon 2 (CRYSTAL, FIRE-3) sometimes from available tissue to test (CALGB 80405). %
Only 430 patients were evaluable for other RAS mutations; %%
475 patients were tested successfully for the other KRAS mutations; $
Extended RAS analysis was performed in
250 patients with 233 patients with KRAS or RAS results. Out of the 221 patients with KRAS exon 2 wt at this stage, 170 were RAS wt; $$
Out of 670 patients tested for all RAS; £592 patients if only those receiving study treatment are considered and 493 patients if only those receiving study treatment and had assessable CT-scan are considered.
EGFR, epidermal growth factor receptor; NA, not available; wt, wild-type
ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17
Final submission draft
30#
Figure 1.
ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17
Final submission draft
31#
Figure 2.
A
Prognostic effect on OS
in the CT + Anti-EGFR Arm
ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17
Final submission draft
32#
B
Prognostic effect on PFS
in the CT + Anti-EGFR Arm
ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17
Final submission draft
33#
C
Prognostic effect on RR
in the CT + Anti-EGFR Arm
ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17
Final submission draft
34#
Figure 3.
A
Prognostic effect on OS
in the CT +/- Bevacizumab Arm
ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17
Final submission draft
35#
B
Prognostic effect on PFS
in the CT +/- Bevacizumab Arm
ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17
Final submission draft
36#
C
Prognostic effect on RR
in the CT +/- Bevacizumab Arm
ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17
Final submission draft
37#
Figure 4.
A
Predictive effect on OS
ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17
Final submission draft
38#
B
Predictive effect on PFS
ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17
Final submission draft
39#
C
Predictive effect on RR
ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17
Final submission draft
16"
are strong negative prognostic markers but might be (non-significant) predictive markers for intensive
therapy [54].
Therefore, with all of the caveats resulting from this analysis, which was performed retrospectively,
and involved a limited number of patients from the individual trials, a relatively small number of right-
sided patients, and – most importantly – did not consider a preference for distinct treatment
sequences, as only the randomization to the respective treatment line was analysed, it provides
evidence in the first-line treatment setting to:
i. Reinforce the use of EGFR antibody therapy in patients with mCRC and left-sided RAS wt
tumours.
ii. Promote the idea that patients with right-sided RAS wt tumours might be better treated with
chemotherapy alone or chemotherapy plus bevacizumab - except maybe if the goal is
tumour size reduction as the ORRs were higher (but not PFS and OS).
iii. Emphasise that in the absence of data on specific treatment sequences, there is no reason
that EGFR-antibody therapy should be avoided in cases of disease progression or treatment
intolerance independent of primary tumour location.
iv. Promote the concept of a “continuum of care” and the sequential use of all therapies,
including bevacizumab where appropriate, in the treatment of patients with mCRC.
However the developmental, genetic, physiological and biological differences associated with the
different locations in the colon and rectum are clearly more complex than simple right- and left-
sidedness and one might predict that a comprehensive evaluation of molecular features in left- and
right-sided CRCs will contribute to improvements in treatment outcomes in the future. Going forward,
new randomised controlled trials should have to stratify patients according to primary tumour location
and if the sequence in which the currently available therapies are delivered matters we need more
trials based on tumour location and molecular characteristics.
acknowledgements
Anne Kinsella (Cancer Communications and Consultancy Ltd, Knutsford, Cheshire UK) is
acknowledged for her assistance in the preparation of the manuscript, funded by ESMO.
funding
All expenses relating to the special symposia were covered by ESMO.
author disclosures
DA has reported honoraria/consultancy for Roche, Merck-Serono, Bayer, Amgen; research funding
from Roche."J-YD has reported advisory boards/symposia/lectures for Amgen, Roche, Merck-Serono,
Sanofi and Bayer. MP has reported honoraria/consultancy/advisory boards for Amgen, Bayer, Sanofi
ESMO Special Symposia manuscript for submission to Annals of Oncology 06.02.17
Final submission draft
16"
are strong negative prognostic markers but might be (non-significant) predictive markers for intensive
therapy [54].
Therefore, with all of the caveats resulting from this analysis, which was performed retrospectively,
and involved a limited number of patients from the individual trials, a relatively small number of right-
sided patients, and – most importantly – did not consider a preference for distinct treatment
sequences, as only the randomization to the respective treatment line was analysed, it provides
evidence in the first-line treatment setting to:
i. Reinforce the use of EGFR antibody therapy in patients with mCRC and left-sided RAS wt
tumours.
ii. Promote the idea that patients with right-sided RAS wt tumours might be better treated with
chemotherapy alone or chemotherapy plus bevacizumab - except maybe if the goal is
tumour size reduction as the ORRs were higher (but not PFS and OS).
iii. Emphasise that in the absence of data on specific treatment sequences, there is no reason
that EGFR-antibody therapy should be avoided in cases of disease progression or treatment
intolerance independent of primary tumour location.
iv. Promote the concept of a “continuum of care” and the sequential use of all therapies,
including bevacizumab where appropriate, in the treatment of patients with mCRC.
However the developmental, genetic, physiological and biological differences associated with the
different locations in the colon and rectum are clearly more complex than simple right- and left-
sidedness and one might predict that a comprehensive evaluation of molecular features in left- and
right-sided CRCs will contribute to improvements in treatment outcomes in the future. Going forward,
new randomised controlled trials should have to stratify patients according to primary tumour location
and if the sequence in which the currently available therapies are delivered matters we need more
trials based on tumour location and molecular characteristics.
acknowledgements
Anne Kinsella (Cancer Communications and Consultancy Ltd, Knutsford, Cheshire UK) is
acknowledged for her assistance in the preparation of the manuscript, funded by ESMO.
funding
All expenses relating to the special symposia were covered by ESMO.
author disclosures
DA has reported honoraria/consultancy for Roche, Merck-Serono, Bayer, Amgen; research funding
from Roche."J-YD has reported advisory boards/symposia/lectures for Amgen, Roche, Merck-Serono,
Sanofi and Bayer. MP has reported honoraria/consultancy/advisory boards for Amgen, Bayer, Sanofi
Pan-Asia adapted ESMO consensus guidelines
for the management of patients with metastatic
colorectal cancer
JSMO/ESMO joint initiative endorsed by CSCO, KACO,
MOS, SSO and TOS
Expert Face-to-Face Meeting
Kobe, July 30, 2017
My first line treatment choices in February 2018
(in fit patients)
Goal Mutation Preferred first line option
Cytoreduction RAS and
BRAF WT
Left: DOUBLET + anti-EGFR
Right: FOLFOXIRI + bevacizumab
(DOUBLET + anti-EGFR?)
RAS mut FOLFOXIRI + bevacizumab
BRAF mut FOLFOXIRI + bevacizumab
Disease
stabilization
RAS and
BRAF WT
Left: DOUBLET + anti-EGFR
Right: FOLFOXIRI or DOUBLET + bevacizumab
RAS mut FOLFOXIRI or DOUBLET + bevacizumab
BRAF mut FOLFOXIRI + bevacizumab